The safety and efficacy of a 4-day myeloablative conditioning (MAC) regimen consisting of Bu 3.2 mg/kg and fludarabine 40 mg/m2/day for HLA-identical sibling allogeneic hematopoietic cell transplantation (HCT) in myeloid malignancies was investigated in 133 patients (median age, 47 years; range 19–74 years) with de novo AML (60%), secondary AML (20%) or myelodysplastic syndrome (20%). All patients engrafted. Hepatic veno-occlusive disease occurred in five patients (4%), and severe toxicities, mostly mucositis, occurred in twenty-three (17%) patients. The non-relapse mortality (NRM) at 100 days was 1.5%. The incidences of acute GVHD grade 2–4 and grade 3–4 were 32 and 13%, respectively. At a median follow-up of 38 months, the cumulative incidence of chronic GVHD was 67%. The relapse incidence was 30% (27 and 31%, respectively, in patients with early- and late-stage disease), and the overall NRM was 15%. The actuarial 4-year disease-free survival (DFS) and overall survival (OS) were 54 and 62%, respectively. Patients aged <50 years had better outcomes compared with older patients (DFS 64 vs 42%, P=0.006; OS 73 vs 47%, P<0.001, respectively).
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for patients with AML or myelodysplastic syndromes (MDS). However, such procedures are associated with the risk of death and morbidity related to the toxicities inherent to the transplant procedure.
The selection of an appropriate conditioning regimen is an important decision, as it must facilitate the engraftment of donor stem cells, but also provide the antineoplastic effect needed to prevent relapse until a graft-versus-tumor effect is fully operative. The classical myeloablative conditioning (MAC) regimens are optimal for young and fit patients. The combination of Bu with Cy is considered standard for chemotherapy-based regimens,1, 2, 3, 4 and is utilized more often than TBI-based regimens, although the effectiveness of the two approaches is roughly similar.5, 6, 7, 8 Intravenous Bu (i.v. Bu), with a more predictable bioavailability than oral formulation, has improved the safety profile of BuCy,9, 10, 11 but without general improvements in survival compared with TBI.12, 13 MAC regimens such as BuCy or CyTBI would not be advisable for elderly or frail patients due to regimen-related toxicities and an enhanced risk of infections and GVHD, all which contribute to increased non-relapse mortality (NRM).14, 15 Incorporation of fludarabine (Flu) combined with other cytotoxic agents in attenuated doses, the so-called reduced intensity conditioning (RIC) regimens, has enabled patients unsuitable for MAC regimens to safety undergo HSCT procedures.16, 17 However, RIC regimens may result in increased relapse rates,18 reflecting their limited antineoplastic effect. The combination of i.v. Bu, in full myeloablative dose with Flu, the so-called reduced toxicity BuFlu regimen, takes advantage of the lower non-hematologic toxicity of Flu compared with Cy.19, 20
The BuFlu regimen might be the preferred conditioning for patients deemed to be at increased risk of toxicities with BuCy because of advanced age or comorbidities,21, 22 and for others in whom an RIC regimen may be associated with an unacceptable risk of relapse after HSCT.23
In this study, we aimed to investigate the safety and efficacy of the BuFlu regimen in adult patients with AML and MDS, transplanted from an HLA-identical sibling. We utilized the i.v. once-daily dose of Bu, a dosing considered equivalent and more convenient than the daily dose divided into four, every 6 h.20, 24
Patients and methods
This was a multicenter, single-arm trial. The study (GET-BUF-2010-02, NCT01683123) was approved by the ethics committee in all participating institutions.
Eligible patients were adults with AML or MDS submitted to allogeneic HSCT from an HLA-identical sibling donor. Patients provided written informed consent, and were required to have adequate cardiac left ventricular ejection fraction (>39%), pulmonary diffusion capacity (diffusing lung carbon monoxide (DLCO) >39%), liver and renal function tests grade 0 to 1 according to Common Terminology Criteria for Adverse Events (CTCAE) V4 and the absence of coexisting infection or other neoplasm requiring therapy.
BuFlu conditioning regimen
The regimen consisted of fludarabine 40 mg/m2 given daily for 4 days (−6 to −3) as a 1-h i.v. infusion (total dose 160 mg/m2) followed immediately by busulfan (Busilvex, Pierre Fabre Médicament, Boulogne, France) 3.2 mg/kg once given daily on the same 4 days (−6 to -3) as a 3-h i.v. infusion (total dose 12.8 mg/kg). Drug doses were calculated from adjusted ideal weight in overweight patients. No drug monitoring for targeting the Bu dose was performed.
Seizure prophylaxis and other supportive measures were applied according to the local standard operating procedures. GVHD prophylaxis consisted of the combination of CYA given orally or i.v. every 12 h to maintain a target blood level of 150–300 ng/ml, and methotrexate i.v., 15 mg/m2 on day +1 and 10 mg/m2 on days +3 and +6. The grafts were obtained from bone marrow or peripheral blood, and were infused into the recipient without selection procedures. No specific prophylaxis for veno-occlusive disease (VOD) was delivered in any of the participating transplant centers.
AML and MDS were classified according to the World Health Organization classification. Secondary AML was defined as AML that was therapy-related or derived from previous MDS. The AML cytogenetic anomalies were classified by the risk classification of the European Leukemia Net.25 Treatment outcomes before HSCT were assessed according to the revised standard criteria.26 CR was defined as bone marrow blasts <5% and the absence of extramedullary disease and normalized blood counts. CRi (CR with incomplete recovery) was defined as above but with residual neutropenia or thrombocytopenia. Disease status and risk categories at transplantation were classified according to Armand et al.27 The hematopoietic cell transplantation (HCT)-CI score28 was used to grade comorbidities. Engraftment was the first day with an absolute neutrophil count more than 0.5 × 109/L. Platelet engraftment was the first day with 20 × 109/L or more, without transfusions. Regimen-related toxicities were graded according to CTCAE V4, except for mucositis, which was graded according to Bearman criteria,29 and hepatic VOD, which was defined by the Baltimore criteria.30 Acute GVHD and chronic GVHD were assessed and graded using the Consensus Conference guidelines.31, 32, 33
The primary safety end point was NRM at 100 days and at the final evaluation with a median observation time of more than 3 years. The primary efficacy end points were rate of disease progression or relapse (RR), disease-free survival (DFS) and OS. Secondary end points were the rate of engraftment, regimen-related toxicities, acute and chronic GVHD incidence and outcome, and the analysis of prognostic factors.
The probabilities of NRM, GVHD and RR were estimated by the cumulative incidence method.34, 35 For analyses of relapse, death in CR was considered as a competing cause of failure. Relapse and death were considered competing events for GVHD, whereas relapse was the competing event for NRM. Unadjusted time-to-event analyses were performed using the Kaplan–Meier estimate,36 with log-rank tests used for comparisons.37 All tests were two-sided, with a significance level of P<0.05. The last follow-up visit was on 15 June 2013. Cox proportional hazards model38 or the Fine and Gray method for competing events39 was used for multivariate analysis using variables with P<0.10 for each end point. The variables analyzed were age, gender, CMV status, diagnosis, cytogenetic risk group, disease stage, and risk category at time of transplantation. Chronic GVHD was considered as a time-dependent variable. Continuous variables were dichotomized at the most discriminant cutoff point for each outcome. Statistical analyses were conducted using R version 2.12.2 (The CRAN project) with packages, survival v2.36-10, Design 2.3-0, prodlim v1.2.1 and cmprsk v2.2-2.40
Disease, patient, donor and transplant characteristics are described in Table 1. Briefly, 133 patients were included. The median age was 47 years (range, 19–74 years). Fifty-six patients (42%) were over 50 years old. Diagnoses were as follows: de novo AML 80 (60%), secondary AML 27 (20%) and MDS 26 (20%). AML was classified according to the cytogenetic risk classification of the European Leukemia Net as follows: favorable, 5%; intermediate 1, 66%; intermediate 2, 10% and high risk, 19%. The genetic risk was high in 42% of MDS patients according to the International Prognostic Scoring System categories. Ninety-one recipients (68%) were transplanted in early stages of the disease: 62 with de novo AML and 17 with secondary AML in CR1 and 12 with MDS untreated or in CR1. Overall, 99 patients (74%) were in CR or CRi, either in first or in subsequent, at HSCT.
Engraftment and safety
The graft source was peripheral blood in 101 patients (76%) and bone marrow in 32 patients (24%). All patients engrafted, with a median time for absolute neutrophil count >500 of 15 days (range, 6–26 days), and for platelets >20 000 of 10 days (range, 5–49 days). Early toxicity attributed to the conditioning regimen is described in Table 2. The most common toxicity was mucositis, which was grade 2 in 55 patients (41%) and grade 3 in 17 patients (13%) and required parenteral nutrition. Other grade 3–4 toxicities were observed in five patients (4%). Hepatic VOD was observed in five patients (4%). Three patients had mild VOD that resolved spontaneously, one patient had moderate VOD that resolved with defibrotide and one patient had severe VOD that improved with defibrotide, but this patient subsequently died due to sepsis. The overall regimen-related toxicity in 56 patients aged over 50 years or in 28 patients with an HCT-CI higher than 2 was similar to that of patients with favorable factors. Median time to hospital discharge from transplant date was 23 days (range, 7–132 days).
Acute GVHD occurred in 65 of 133 evaluable patients (48.8%). The distribution of clinical grades was as follows: grade I (16.5%), grade II (19.5%), grade III (9%) and grade IV in five (3.8%). The median time to the development of grade II–IV acute GVHD was 34 days (range, 12–140 days). The cumulative incidence of grade II–IV and grade III–IV acute GVHD at day 140 after transplantation was 32% (95% confidence interval (CI); 24–40%) and 13% (95% CI; 7–19%), respectively. Older age was significantly associated with higher risk of acute GVHD. The cumulative incidence of grade III–IV acute GVHD at 140 days was 8 and 20% for patients 50 years or less and older than 50 years, respectively (P=0.04).
In all, 84 of 125 at-risk patients developed chronic GVHD. Chronic GVHD was limited in 24 patients and extensive in 60 patients. The median time to onset of chronic GVHD was 6 months days (range, 1–26 days). The 4-year cumulative incidence for all types of chronic GVHD and extensive disease was 68% (95% CI; 59–78%) and 42% (95% CI; 33–51%), respectively. No variable was identified as a prognostic factor for the development of chronic GVHD. Older age was significantly associated with higher risk of chronic extensive GVHD. The 4-year cumulative incidence of chronic extensive GVHD was 34 and 54% for patients 50 years or less and older than 50 years, respectively (P=0.01).
NRM and causes of death
Two patients (1.5%) died before day 100, one due to acute GVHD and one due to sepsis. Overall, 20 patients (15%) died without evidence of relapse at a median of 6 months (range, 1–20 months). The NRM at 3, 6, 12 and 48 months was 1.5, 8, 11 and 15%, respectively.
In the univariate analysis, older age, male gender, secondary AML and advanced disease stage were associated with NRM. In the multivariate analysis, older age and secondary AML remained significantly associated with increased NRM. The NRM incidence increased progressively with age (Figure 1). The 4-year cumulative incidence of NRM was 5, 11 and 25% for patients ⩽40, 41–50 and >50 years, respectively (P=0.02). The 4-year NRM was 30% for patients with secondary AML compared with 13% for MDS or de novo AML (P=0.03).
The overall mortality in this series was 47 (35.3%) and the causes of death were as follows: relapse 27 (20.3%); GVHD 11 (8.3%), infection 7 (5.3%) and unknown 2 (1.5%).
Thirty-eight patients relapsed at a median time of 6 months (range, 1–36 months). The 4-year cumulative incidence of relapse was 30% (95% CI, 22–39 months). Disease-related factors such as type of disease, cytogenetic risk and stage at HSCT were not associated with an increased risk of relapse. The 4-year cumulative incidence of relapse for patients transplanted in advanced phase was 27% (95% CI, 11–43%) and 31% (95% CI, 22–41%) for those transplanted in earlier stages. In the analysis restricted to patients with AML, high-risk cytogenetics were associated with a decreased DFS (relative risk 0.5; 95% CI, 0.3–0.9; P=0.04). The cumulative incidence of DFS at 4 years for patients with AML with or without high-risk cytogenetics was 39 and 59%, respectively (P=0.04) (Figure 2).
DFS and OS
Seventy-five patients (56.4%) remained alive and leukemia free after transplantation at the final analysis (range, 12–84 months). The median follow-up for surviving patients was 38 months (range, 12–84 months). The 4-year DFS was 54% (95% CI, 45–63%). The 4-year OS was 62% (95% cumulative incidence, 53–71%). In the multivariate analysis of prognostic factors, the only factor associated with increased NRM and reduced DFS and OS was age. Secondary AML was associated with increased NRM. Given that the median age was 47 years in this series, we selected a cutoff of 50 years at transplantation to define two groups with different risks for DFS (relative risk 0.7; 95% cumulative incidence, 0.6–0.9) and OS (relative risk 0.6; 95% cumulative incidence, 0.5–0.8) (Table 3). The 4-year DFS for patients up to 50 years or older than 50 years was 64 and 42%, respectively (P=0.006). The 4-year OS for the same age groups was 73 and 47%, respectively (P<0.001) (Figure 3).
This study shows that i.v. BuFlu regimen is well tolerated in adults with AML or MDS undergoing allogeneic HSCT from HLA-identical matched-sibling donors, and has a low NRM (<2% at 100 days and 15% at 4 years). The favorable safety outcomes in the early period after HSCT allowed transplant teams to establish effective disease control and achieve good long-term survival. These advantages were seen in patients with both early and advanced phases of disease. As expected, age was an important risk factor for NRM, and in this study was closely associated with a higher incidence of acute and chronic GVHD.
The initial reports with BuFlu conditioning all supported the improved safety of the regimen, with low NRM at 1 year while preserving the antitumor activity.19, 20 It is important to emphasize that, as opposed to the BuCy regimen, there is no uniform schedule for the BuFlu regimen. We utilized the sequence of fludarabine followed by Bu, as first designed, since it seemed optimal for engraftment and outcome. In one study, NRM after BuFlu conditioning was reduced, but older patients had more GVHD-related deaths than younger ones.41 Retrospective comparisons of different conditioning regimens in patients with aged over 55 years suggested improved long-term outcome with BuFlu over BuCy in one study21 while the NRM with BuFlu was similar to that reported with RIC regimens in another.22
In this study, we evaluated the BuFlu regimen in a homogeneous series of patients with AML or MDS receiving HSCT from HLA-identical matched-sibling donors and uniform GVHD prophylaxis reducing the impact of other types of diseases and donors or prophylactic procedures. Patients were consecutively recruited in the institutions and entered long-term follow-up lasting more than 3 years to capture long-term adverse events. The patient population included 42% aged over 50 years and 23% with advanced disease stage at transplantation. BuFlu regimen was well tolerated. The most frequent toxicity was mucositis, but only 13% of patients required parenteral nutrition and 46% had minimal or no mucositis at all. The use of GVHD prophylaxis with methotrexate is known to worsen regimen-related mucositis and gastrointestinal toxicity but, notably, the gastrointestinal toxicity in this series was minimal. Patients receiving Bu containing regimens are specifically monitored regarding liver toxicity, in particular VOD. Twelve of our patients (9%) had liver toxicity grade 2–4, including seven patients with increased transaminases and five patients (4%) fulfilling criteria for VOD. Three patients with VOD had a mild course and resolved spontaneously, and two patients with moderate and severe forms were treated satisfactorily with defibrotide. The incidence of VOD with BuFlu is generally lower than 5%, and this effect is also in agreement with the reported observation of a reduction in the incidence of VOD over time.42 VOD is expected to be less frequent and severe with the use of i.v. compared with oral Bu, with RIC compared with MAC, and with BuFlu compared with BuCy conditioning.43, 44
The 1.5% early NRM found in our study confirms the low toxicity profile of this regimen. With BuFlu, early mortality can be reduced in patients with advanced age or disease status and even in heavily pretreated patients. The incidence of grade 3–4 acute GVHD was also low, and similar to previous studies with BuFlu.20, 22, 45 It has been suggested that the improved tolerance of BuFlu contributes to reduced early infection rates and acute GVHD incidence, and minimizes the impact on survival of prior comorbidities at HSCT.46 Acute and chronic GVHD had an impact on outcomes in this study, and the incidence and course of these events were probably not specifically related to the selection of BuFlu as conditioning regimen. Chronic GVHD is more frequent in older patients and has a marked impact on the late NRM after HSCT. Acute or chronic GVHD contributed to NRM in 85% of our patients due either to GVHD complications or to opportunistic infections. New strategies in GVHD prophylaxis could assist in the protection of older patients from GVHD and its impact on NRM. Incorporation of antithymocyte globulin, sirolimus,47 and post-transplantation CY48 have been investigated as valuable tools to improve this outcome.
An unexpected observation in this study was the lack of differences in the long-term outcome by disease type or disease stage at HSCT, as the relapse rate in advanced stages was close to that in early stages. However, the groups were not of a similar size and other possible explanations, such as a rapid taper in CYA, could have contributed to the anti-leukemic efficacy of the transplantation regimen in patients with advanced disease at the expense of increased GVHD and related complications. In fact, patients aged over 50 years had a lower survival probability due to NRM, and this was directly related to GVHD.
The potential advantages of BuFlu have raised the possibility of replacement of the more conventional conditioning regimens. In a retrospective CIBMTR study, a better 2-year OS was shown with i.v. Bu compared with TBI, but importantly in the i.v. Bu cohort, BuCy and BuFlu had similar NRM and OS, despite the older age of the BuFlu population.49 Three prospective studies have specially compared BuCy with BuFlu. In a trial including 126 adults with AML, ALL or MDS, both regimens showed similar NRM and OS.50 In another trial including 108 patients with AML, a favorable NRM was shown with BuFlu versus BuCy, although DFS was similar at 5 years.51 Finally, in the most recently reported study in AML patients aged 40–65 years, BuCy showed higher 1-year NRM versus BuFlu but no differences in 5-year DFS.52 The results therefore supported improved safety with BuFlu compared with BuCy but this did not confer any real advantage in terms of survival. Another area of interest is the role of BuFlu as an alternative to RIC regimens in elderly patients, a population who would be suitable for both types of conditioning.23 The rational is that higher doses of Bu used in the BuFlu are not expected to cause higher toxicity,53 and that RIC regimens rely on the chronic GVHD-associated anti-tumor effect to achieve improvements in DFS.54
In summary, the BuFlu conditioning regimen in adults with AML or MDS, in the HLA-identical sibling HSCT setting, is well tolerated and applicable even in advanced phases. We believe that this convenient conditioning platform merits further investigation in combination with new strategies aimed at decreasing the impact of GVHD-related adverse events, an unmet need to improve the HSCT outcome.
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We greatly appreciate the participation of all the patients and their families. We are indebted to the contributing members of the GETH at the participating institutions, and nurses, data managers and physicians of the HCT teams at contributing sites. We specially thank Mr Luis Benlloch, GETH Data Manager, for data collection and database assembly. We also thank Dr Gregory Morley for editorial assistance. This clinical trial was funded in part by an educational grant from Pierre-Fabre Iberica Pharmaceutical. This company was not involved in the design and running of the trial, nor in the collection and analysis of the clinical data, and the final manuscript.
The authors declare no conflict of interest.
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De La Serna, J., Sanz, J., Bermúdez, A. et al. Toxicity and efficacy of busulfan and fludarabine myeloablative conditioning for HLA-identical sibling allogeneic hematopoietic cell transplantation in AML and MDS. Bone Marrow Transplant 51, 961–966 (2016). https://doi.org/10.1038/bmt.2016.42
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